Pancreatic cancer is the 4th leading cause of cancer-related deaths in the U.S., with over 28,000 fatalities occurring each year. From the time of diagnosis the median survival ranges from 3 to 6 months, giving pancreatic cancer patients the most dismal prognosis of all malignancies. The reasons for this poor outlook are partially due to the nature of the cancer in that it is notoriously resistant to radiation therapy and chemotherapy, and the fact that the cancer is not diagnosed in early stages when surgical resection is an option. Our research group has been studying strategies for early diagnosis and treatment. In preliminary studies we have found that endogenous (native) opioid peptides interact with opioid receptors associated with human pancreatic cancer cells to inhibit growth in vitro and in vivo. Our investigations have documented the opioid growth factor (OGF). [MET/5]-enkephalin, is involved in the growth of pancreatic cancer, and has a reversible action on tumorigenic events that serves to repress growth. OGF's action is mediated by the opioid receptor, zeta. This grant hypothesizes that administration of OGF will change the course of pancreatic cancer in human subjects by acting as an inhibitory agent. We propose to investigate this hypothesis by an open-labelled Phase 1 clinical trial to establish the maximum-tolerance dose, and evaluate the safety, biological effects, and drug-related toxicities of OGF in human subjects. The following specific aims are proposed: 1) Determine the maximum-tolerated dose of OGF in cancer patients after an intravenous infusion, the effects of subcutaneous administration of OGF in patients with cancer, 4) Evaluate the repercussions and begin to investigate efficacy of chronic administration of OGF on patients with pancreatic cancer, and 5) Elucidate the relationship between OGF plasma levels and tumor progression in patients with pancreatic cancer. These studies are part of a long-range program directed toward understand the mechanism and treatment of pancreatic oncogenesis, particularly the cellular and molecular biology of peptides that serve as growth factors.